TAAR1 Expression and Signaling in the Immune System: A Potential Novel Immunomodulator in Multiple Sclerosis.

Background: In addition to its defined neuroregulatory properties, emerging evidence suggests trace amine-associated receptor 1 (TAAR1) as a potential novel therapeutic target for immunomodulatory disorders. Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. I hypothesized that TAAR1 may be differentially expressed in immune cells derived from MS patients and mediates key cell-specific pathophysiological events related to MS pathogenesis.
Methods: RT-qPCR was used to measure TAAR1 mRNA in peripheral blood mononuclear cells (PBMCs) of healthy controls (N = 15, Age = 51 ± 7, F:M = 1.16), non-inflammatory neurological disorder patients (NIND; N = 10, Age = 47 ± 1, F:M = 2.67), and drug-naïve relapse-remitting MS patients (N = 14, Age = 44 ± 9, F:M = 1.85).
To address the function of TAAR1, mouse bone marrow-derived macrophages (BMDMs) and human monocyte-derived macrophages (MDMs) were simultaneously treated with LPS (100 ng/mL) and the selective TAAR1 agonist RO5256390 (1-300 nM) for 6 hours and total secreted levels of tumor necrosis factor (TNF) determined via ELISA. Separately, mouse BMDMs and human fetal microglia were simultaneously treated with ATP (1 mM) and RO5256390 (1-300 nM) for 6 hours. TNF and IL-6 was measured, the metabolic profile determined via a Seahorse™ Real-Time ATP Rate Assay, and cell death measured via a propidium iodide uptake assay.
Results: TAAR1 mRNA expression is higher in NIND patients (p = 0.02, Kruskal-Wallis with Dunn’s post-hoc test) with significantly greater variability in NIND and MS groups (p = 0.03, Brown-Forsythe test). RO5256390 had no effect on LPS-induced TNF secretion from human and mouse macrophages but significantly inhibited ATP-induced TNF secretion (N = 5, p = 0.014) from mouse BMDMs independent of IL-6 secretion and cell death. ATP also induced a glycolytic shift in mouse BMDMs that was unaffected by RO5256390.
Conclusions: Differential TAAR1 expression in MS and NIND PBMC suggests that expression could be a disease subtype biomarker. Since ATP is a more pathologically relevant pro-inflammatory stimuli than LPS, TAAR1 agonism could represent a novel anti-inflammatory therapeutic option in MS. This effect on pro-inflammatory signalling appears to be independent of the associated glycolytic shift.